Diphenyleneiodonium chloride inhibits MYCN-amplified neuroblastoma by targeting MYCN induced mitochondrial alterations

High-risk neuroblastoma is one of the most lethal childhood cancers. Half of these tumors are driven by MYCN gene amplification (MNA). Despite intensive chemo- and radiotherapy, only 40% of patients survive, and they often suffer from long-term side effects of these genotoxic treatments. Thus, less toxic and more efficacious therapies are needed. Here, we identified diphenyleneiodonium chloride (DPI) as tool compound that preferentially targeted MNA neuroblastoma. Using proteomic and metabolomic assays we investigated the DPI mode of action, finding that DPI could target alterations induced by MNA. These included cell cycle progression, DNA repair pathways, and profound changes in the expression of proteins participating in the mitochondrial electron transport chain. In addition, DPI also downregulated MYCN protein levels preferentially in MNA cells. Metabolic and biological assays suggested that alterations in mitochondrial function and the associated production of reactive oxygen species are critical DPI targets. DPI reduced the proliferation, survival, and malignant transformation of MNA neuroblastoma cells. DPI also shrank tumors and prevented metastatic spread in zebrafish models of neuroblastoma. These findings suggest that processes impacted by DPI could be valuable new targets for the development of non-genotoxic drugs against MNA neuroblastoma.